Project Summary Survivors of childhood cancers face multiple late effects of their initial cancer therapy. One of the most difficult and consequential is the occurrence of a subsequent neoplasm. Subsequent breast cancers are the second most frequently observed subsequent neoplasm, exceeded only by non-melanoma skin cancers. Although much attention has been given to subsequent breast cancer risk and risk factors among survivors, there are limited data on treatment, treatment-related toxicities, survival and physician decision making for these challenging subsequent neoplasms. Survivors of childhood cancer have previously been exposed to therapies, including radiation and/or anthracycline chemotherapies, which may limit their ability to safely receive standard-of-care breast cancer therapy. The overall goals of this study will be: 1) to quantify how overall and event-free survival among long-term survivors of childhood cancer who develop a subsequent breast cancer compare to a geographically diverse, age-, race and ethnicity-,breast cancer stage-, and treatment era- matched cohort of women with similar breast cancer characteristics, and how their overall survival compares to SEER survival estimates; 2) to describe how survivors of childhood cancer who develop a subsequent breast cancer are medically managed and how treatment compares to a contemporarily-treated, age-, race and ethnicity-, breast cancer stage-, and treatment era-matched matched comparison cohort and to contemporary National Comprehensive Cancer Network treatment guidelines, and to describe treatment-related toxicities among survivors with subsequent breast cancer and compare the toxicity profile with a matched comparison cohort of women with primary breast cancer; and 3) to describe how breast cancer treatment decisions are made, through semi-structured interviews and surveys, among medical and radiation oncologists. This project will provide data necessary to improve health outcomes in this growing high-risk and vulnerable population of survivors of childhood cancer. Understanding the drivers of decision-making, the way women with subsequent breast cancers are treated, and how their outcomes compare to other women with breast cancer will guide educational interventions and the development of treatment guidelines for women with subsequent breast cancer. The skills developed through the completion of the aims in this proposal, in complex epidemiological study design, qualitative and mixed methods study methodology, and study leadership, will lay the groundwork for leading novel and high-impact survivorship studies. This project will serve as a transition point from working as a mentored physician scientist to an independent investigator, as demonstrated by a planned R01 submission during the final year of this study.